The present invention relates to indan derivatives and pharmaceutically acceptable salts thereof, as well as NF-xcexaB inhibitors. More specifically, the present invention relates to preventive or therapeutic agents for diseases caused by the activation of NF-xcexaB, said agent having as an active ingredient an indan derivative or a pharmaceutically acceptable salt thereof.
Nitric oxide (NO) is biosynthesized from L-arginine as a substrate by NO synthase (NOS). Currently three isozymes of NOS have been found: a brain isozyme (bNOS), an endothelial isozyme (eNOS), and an inducible isozyme (iNOS) (Moncada, S. and Higgs, A. (1993) N. Engl. J. Med. 329: 2002-2012). The gene of iNos is induced by endotoxins and cytokines on macrophages, vascular smooth muscle cells, hepatocytes, chondrocytes, gliacytes, etc. and then its expression comes to be observed (Forstermann, U., Gath, I., Schwarz, P., Closs, E. I. and Kleinert, H. (1995) Biochem. Pharmacol. 50: 1321-1332).
The iNOS has been reported to be induced by inflammatory conditions regardless of the species, and the suppression of the enzymatic activity and the expression has been shown to be useful for amelioration of the disease states (Cattell, V. and Jansen, A. (1995) Histochem. J. 27: 777-784; Nussler, A. K. and Billiar, T. R. (1993) J. Leukoc. Biol. 54: 171-178).
It has been reported that arginine derivatives or aminoguanidine exhibit pharmacological effects in model animals of myocarditis, cerebral infarction, arthritis, sepsis, multiple sclerosis, systemic lupus erythematosus, and insulin-dependent diabetes mellitus (Moncada, S. and Higgs, E. A. (1995) Faseb. J. 9: 1319-1330). Though L-N-monomethyl arginine, a NOS inhibitor, is highly toxic at high doses, it not only improves low blood pressure in sepsis but has a marked preventive effect, on which a clinical trial is under way (Moncada, S. and Higgs, E. A. (1995) Faseb. J. 9: 1319-1330).
Furthermore, resistance against sepsis or inflammation induced by carrageenin has been shown in experiments using knockout mice of iNOS, revealing that the expression of iNOS causes these pathological states (Wei, X. Q., Charles, I. G., Smith, A., Ure, J., Feng, G. J., Huang, F. P., Xu, D., Muller, W., Moncada, S. and Liew, F. Y. (1995) Nature 375: 408-411).
An excess of NO produced by the induction of iNOS expression is believed to damage normal cells and cause various disease states. On the other hand, the constitutively occurring NOS (cNOS) termed eNOS or bNOS is required to suppress an increase in blood pressure and to maintain it. Thus, inhibitors that do not inhibit the activity of cNOS and that inhibit iNOS specifically are required. However, since the regions of the proteins that regulate the enzymatic activity of isozymes are very similar to one another in the primary structure, no NOS inhibitors have yet been found which are sufficiently specific (Ogden, J. E. and Moore, P. K. (1995) Trends Biotechnol. 13: 70-78, Manning, R., Jr., Hu. L., Mizelle, H. L., Montani, J. P. and Norton, M. W. (1993) Hypertension 22: 40-48).
As enzyme inhibitors, L-arginine (and amino acid) derivatives have mainly been developed but many of them are low in isozyme specificity. Although aminoguanidine and amidine derivatives, though weakly effective, have been reported to have relatively iNOS-specific inhibitory effects (Southan, G. J. and Szabo, C. (1996) Biochem. Pharmacol. 51: 383-394), pharmaceutical agents having adequate specificity have yet not to be found.
On the other hand, TNF-xcex1, a cytokine produced by various cells including macrophage, is believed to be an important mediator of inflammation (Vassalli, P. (1992) Annu. Rev. Immunol. 10: 411-452). There is growing evidence that the excessive production of TNF-xcex1 damages normal cells and causes various pathological conditions (Muto, Y., Nouri-Aria, K. T., Meager, A., Alexander, G. J., Eddleston, A. L. and Williams, R. (1988) Lancet 2: 72-74, Sharief, M. R. and Hentges, R. (1991) N. Engl. J. Med. 325; 467-472).
Increases in TNF-xcex1 have been observed in the synovial fluid and the blood of patients with, for example, rheumatoid arthritis (Tetta, C., Camussi, G., Modena, V., Di Vittorio C. and Baglioni, C. (1990) Ann. Rheum. Dis 49: 665-667; Venn, G., Nietfeld, J. J., Duits, A. J., Brennan, F. M., Arner, E., Covington, M., Billingham, M. E. and Mardingham, T. E. (1993) Arthritis Rheum. 36: 819-826). Antibody against TNF-xcex1 has also been demonstrated to be effective in clinical trials (Elliott, M. J., Maini, R. N., Feldmann, M., Long-Fox, A., Charles, P., Bijl, H. and Woody, J. N. (1994) Lancet 344: 1125-1127; Elliott, M. J., Maini, R. N., Feldmann, M., Kalden. J. R., Antoni, C., Smolen, J. S., Leeb, B., Breedveld, F. C., Macfarlane, J. D., Bijl, H. and et al. (1994) Lancet 344: 1105-1110; Rankin, E. C., Choy, E. H., Kassimos, D., Kingsley, G. H., Sopwith, A. M., Isenberg, D. A. and Panayi, G. S. (1995) Br. J. Rheumatol. 34: 334-342).
Furthermore, the involvement of TNF-xcex1 in sepsis or inflammatory bowel diseases has been pointed out and the ameliorating effects of anti-TNF-xcex1 antibody on these diseases have been observed (Vincent, J. L., Bakker, J., Marecaux, G., Schandene, L., Kahn, R. J. and Dupont, E. (1992) Chest 101: 810-815; Hinshaw, L. B., Tekamp-Olson, P., Chang, A. C., Lee, P. A., Taylor, F., Jr., Murray, C. K., Peer, G. T., Emerson, T., Jr., Passey, R. B. and Kuo, G. C. (1990) Circ. Shock 30: 279-292).
These findings expressly indicate that the excessive production of TNF-xcex1 causes and aggravates various inflammations, therefore the development of pharmaceutical agents that can inhibit the production of TNF-xcex1 (Nyman, U., Mussener, A., Larsson, E., Lorentzen, J. and Klareskog, L. (1997) Clin. Exp. Immunol. 108: 415-419) is required.
Thus, iNOS or TNF-xcex1 have been recognized to be one of the causes of various inflammations. However, the fact that many other mediators have been demonstrated to cause inflammation and thereby the cause of the diseases cannot be attributed to any one particular mediator makes the development of therapeutic agents difficult. Under these circumstances, there is a great need for low molecular weight compounds that not only suppress the expression of particular proteins but inhibit widely the production and expression of proteins involved as causative factor in the inflammation.
NF-xcexaB is a protein that regulates gene expression and is one of the so-called transcription factors. Normal cells, when stimulated with inflammatory cytokines such as interleukin-1 (IL-1) and TNF-xcex1, a lipopolysaccharide, or ultraviolet rays, NF-xcexaB is activated and then it translocates from the cytoplasm into the nucleus where it binds to specific nucleotide sequences on the genomic DNA and thereby become involved in the expression of various genes (Blackwell, T. S. and Christman, J. W. (1997) Am. J. Respir. Cell Mol. Biol. 17: 3-9).
Genes encoding iNOS and TNF-xcex1, though entirely different from one another, have regions to which NF-xcexaB binds on the expression control region of the genomic gene thereof, and there is growing evidence that the activation of NF-xcexaB is important for the expression of these proteins in common (Jongeneel, C. V. (1994) Prog. Clin. Biol. Res. 388: 367-381; Xie, Q. w., Kashiwabara, Y. and Nathan, C. (1994) J. Biol. Chem. 269: 4705-4708; Nunokawa, Y., Oikawa, S. and Tanaka, S. (1996) Biochem. Biophys. Res. Commun. 223: 347-352).
Many genes that are involved in immunological inflammatory reactions under expression control by NF-xcexaB are recognized, in addition to iNOS and TNF-xcex1, ones for inflammatory cytokines such as IL-1, IL-6 and IL-8, as well as cell adhesion factors such as ICAM-1, VCAM-1 and ELAM-1 or the like (Collins, T., Read, M. A., Neish, A. S., Whitley, M. Z., Thanos, D. and Maniatis, T. (1995) Faseb. J. 9: 899-909). Furthermore, it is known that inflammatory cytokines, when bound to receptors, transduce NF-xcexaB-activating signals via various routes, and this fact is believed to be cause that further aggravates inflammation. Thus, the activation of NF-xcexaB in inflammation is understood as an etiological and aggravating matter of diseases (Baeuerle, P. A. and Baichwal., V. R. (1997) Adv. immunol. 65: 111-137).
In recent years, it has also been reported that HIV, HTLV-1, CMV, adenovirus and the like activate NF-xcexaB in the host cell (Dezube, B. J., Pardee, A. B., Beckett, L. A., Ahlers, C. M., Ecto, L., Allen-Ryan, J., Anisowicz, A., Sager, R. and Crumpacker, C. S. (1992) J. Acquir. Immune Defic. Syndr. 5: 1099-1104; Nabel, G. and Baltimore, D. (1987) Nature 326: 711-713; Fazely, F., Dezube, B. J., Allen-Ryan, J., Pardee, A. B. and Ruprecht, R. M. (1991) Blood 77: 1653-1656; Munoz, E. and Israel, A. (1995) Immunobiology 193: 128-136). The activation of NF-xcexaB in turn activates its transcription leading to the progression of viral propagation and infection.
Accordingly, it is possible to suppress altogether the induction of expression of these inflammatory cytokines, genes of adhesion molecules, and viruses by inhibiting the activation of NF-xcexaB, and NF-xcexaB inhibitors are promising as therapeutic agents of such diseases as are caused either directly or indirectly by the activation of NF-xcexaB, specifically various inflammatory diseases, autoimmune diseases and viral diseases, and immunosuppressive agents.
Therapeutic agents currently used for chronic diseases such as rheumatism include steroid hormones such as glucocorticoids, non-steroidal aspirin formulations, and the like. However, glucocorticoids are known to be associated with the appearance of severe side effects such as the aggravation of infectious diseases, onset of peptic ulcer, and central effects, and therefore are not amenable to a long-term administration. Furthermore, although the non-steroidal agents suppress the production of prostaglandins etc., they do not provide curative treatments and they are known to exhibit such side effects as the onset of peptic ulcer and central effects.
It has also been reported in recent years that anti-inflammatory drugs at high doses inhibit the activation of NF-xcexaB (Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A. and Karin, M. (1995) Science 270: 286-290; Shackelford, R. E., Alford, P. B., Xue, Y., Thai, S. F., Adams, D. O. and Pizzo, S. (1997) Mol Pharmacol. 52: 421-429; Bitko, V., Velazquez, A., Yang, L, Yang, Y. C. and Barik, S. (1997) Virology 232: 369-378). However, due to their diverse pharmacological actions, these compounds have side effects, and therefore the development of safer drugs based on a novel mechanism is required.
As a method of inhibiting the actions of TNF-xcex1, it is thought that the use of antibodies that specifically bind to TNF-xcex1 and TNF receptor proteins. However, those are both macromolecule proteins and are not suitable for oral administration.
Currently, several compounds are known as NF-xcexaB inhibitors, including, for example, substituted pyrimidine derivatives (International Patents Publication WO9709315, WO9709325, J. Med. Chem., 41, 413 (1998)), xanthine derivatives (Japanese Unexamined Patent Publication (kokai) No, 9-227561), isoquinoline derivatives (Japanese Unexamined Patent Publication (Kokai) No. 10-87491), and the like. However, truly effective drugs have yet to be found.
Several compounds are known as indan derivatives, including, for example, adenosine derivatives that have the antihypertensive actions (Japanese Unexamined Patent Publication (Kokai) No. 2-184649, J. Med. Chem., 34, 1043 (1991)), adenosine derivatives that have the antiallergic actions (Japanese Unexamined Patent Publication (Kokai) No. 60-193998), quinazoline derivatives that have the antidepressant actions (U.S. Pat. No. 3,470,182), and the like. However, a compound that inhibits the activation of NF-xcexaB have not been known yet.
Furthermore, though heterocyclic compounds that have the effect of inhibiting NO production were published recently (Japanese Unexamined Patent Publication (Kokai) No. 10-87492), they do not address the problem of inhibiting NF-xcexaB activation. Compounds published therein are different from the those of the present invention that are represented by the general formula (I) on the substituents of the pyrimidine ring and the amino groups.
The present invention provides preventive and therapeutic agents for diseases caused by the activation of NF-xcexaB, for example, diseases caused by the excessive production of various inflammatory mediators and viral propagation, by inhibiting the activation of NF-xcexaB. More specifically, it provides therapeutic and preventive agents for diseases that are believed to be caused by the excessive production of NO or TNF-xcex1 including, for example, sepsis, osteoarthritis, rheumatoid arthritis, cachexia, multiple organ failure, inflammatory bowel diseases, malaria, acquired immune deficiency syndrome, human T-cell leukemia, meningitis, hepatitis, type II diabetes, multiple sclerosis, Behcet disease, systemic lupus erythematosus; ischemic heart diseases such as myocardial infarction, cerebral ischemic diseases and neurodegenerative diseases such as Alzheimer""s disease, and the like.
As a result of intensive studies on substances that inhibit the activation of NF-xcexaB, the present inventors have found that indan derivatives represented by the general formula (I) or pharmaceutically acceptable salts thereof potently inhibit the activation of NF-xcexaB and that they inhibit the production of NO and TNF-xcex1 on the gene a level, and thereby have accomplished the present invention.
Thus, the present invention relates to indan derivatives represented by the following the general formula (I): 
wherein
R1 represents a hydrogen atom or an alkyl group having 1 to 4 carbons, and
R2 represents a hydrogen atom,
a xe2x80x94OR3 group (in the group, R3 represents a hydrogen atom, an alkyl group having 1 to 7 carbons, an optionally substituted phenyl group, an optionally substituted bicyclic unsaturated or partially saturated hydrocarbon ring group having 9 to 11 carbons, an optionally substituted aralkyl group having 7 to 11 carbons, or a xe2x80x94(CH2)n A group (n is 0, or an integer of 1, 2 or 3, and A is a heterocyclic group)],
a xe2x80x94OCOR4 group [in the group, R4 represents a hydrogen atom, an alkyl group having 1 to 7 carbons, an optionally substituted phenyl group, an optionally substituted bicyclic unsaturated or partially saturated hydrocarbon ring group having 9 to 11 carbons, an optionally substituted aralkyl group having 7 to 11 carbons, or a xe2x80x94(CH2)n A group (n is 0, or an integer of 1, 2 or 3, and A is a heterocyclic group)],
a xe2x80x94COOR5 group [in the group, R5 represents a hydrogen atom, an alkyl group having 1 to 7 carbons, an optionally substituted phenyl group, an optionally substituted bicyclic unsaturated or partially saturated hydrocarbon ring group having 9 to 11 carbons, an optionally substituted aralkyl group having 7 to 11 carbons, or a xe2x80x94(CH2)n A group (n is 0, or an integer of 1, 2 or 3, and A is a heterocyclic group)],
a xe2x80x94CONR6R7 group [in the group, R6 and R7, which may be the same or different, each represent a hydrogen atom, an alkyl group having 1 to 7 carbons, an optionally substituted phenyl group, an optionally substituted bicyclic unsaturated or partially saturated hydrocarbon ring group having 9 to 11 carbons, an optionally substituted aralkyl group having 7 to 11 carbons, or a xe2x80x94(CH2)n A group (n is 0, or an integer of 1, 2 or 3, and A is a heterocyclic group), or R6 and R7, together with the nitrogen atom to which they are attached, represent a heterocyclic group that may further contain a nitrogen atom, an oxygen atom, or a sulfur atom], or
a xe2x80x94CHxe2x95x90CHR8 group (in the group, R6 represents an alkyl group having 1 to 4 carbons, or an optionally substituted phenyl group), and 
xe2x80x83represents a skeleton selected from the group consisting of 
wherein R9 and R10, which may be the same or different, each represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, an optionally substituted amino group, an optionally esterified or amidated carboxyl group, an alkyl group having 1 to 4 carbons, an alkyloxy group having 1 to 4 carbons, an optionally substituted phenyl group, an optionally substituted aralkyl group having 7 to 11 carbons, or an optionally substituted heterocyclic group, or R9 and R10 together form 
xe2x80x83and X represents an oxygen atom or a sulfur atom;
pharmaceutically acceptable salts thereof, NF-xcexaB inhibitors, inhibitors of TNF-xcex1 production, and inhibitors of NO production containing them as active ingredients, and uses thereof as preventive or therapeutic agents of inflammatory diseases, autoimmune diseases, and viral diseases and/or immunosuppressive agents.